Gamma Tocopherol Upregulates the Expression of 15-S-HETE and Induces Growth Arrest Through a Ppar Gamma-Dependent Mechanism in PC-3 Human Prostate Cancer Cells

Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that -tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) , a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that -tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR mRNA and protein upregulation was achieved with -tocopherol within 6 h. -Tocopherol-mediated growth arrest was demonstrated to be PPAR dependent using the agonist GW9662 and a PPAR dominant negative vector. -tocopherol was shown not to be a direct PPAR ligand, but rather 15-S-HETE (an endogenous PPAR ligand) was upregulated by -tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following -tocopherol treatment. Expression of proteins downstream of the PPAR pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NF B proteins were found to be downregulated following -tocopherol treatment. These data demonstrate that the growth arrest mediated by -tocopherol follows a PPAR - dependent mechanism